Research output: Contribution to journal › Article › peer-review
Mechanism of the enhancing effect of glycyrrhizin on nifedipine penetration through a lipid membrane. / Kim, A. V.; Shelepova, E. A.; Evseenko, V. I. et al.
In: Journal of Molecular Liquids, Vol. 344, 117759, 15.12.2021.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Mechanism of the enhancing effect of glycyrrhizin on nifedipine penetration through a lipid membrane
AU - Kim, A. V.
AU - Shelepova, E. A.
AU - Evseenko, V. I.
AU - Dushkin, A. V.
AU - Medvedev, N. N.
AU - Polyakov, N. E.
N1 - Funding Information: The study was financially supported by Russian Ministry of Science and Education (projects No 0304-2017-0009 and 0301-2019-0005 ). Publisher Copyright: © 2021 Elsevier B.V.
PY - 2021/12/15
Y1 - 2021/12/15
N2 - The saponin glycyrrhizin from liquorice root shows the ability to enhance the therapeutic activity of other drugs when used as a drug delivery system. Due to its amphiphilic properties, glycyrrhizin can form self-associates (dimers, micelles) and supramolecular complexes with a wide range of hydrophobic drugs, which leads to an increase in their solubility, stability and bioavailability. That is why the mechanism of the biological activity of glycyrrhizin is of considerable interest and has been the subject of intensive physical and chemical research in the last decade. Two mechanisms have been proposed to explain the effect of glycyrrhizin on drug bioavailability, namely, the increase in drug solubility in water and enhancement of the membrane permeability. Interest in the membrane-modifying ability of glycyrrhizic acid (GA) is also growing at present due to its recently discovered antiviral activity against SARS-CoV-2 Bailly and Vergoten (2020) [1]. In the present study, the passive permeability of the DOPC lipid membrane for the calcium channel blocker nifedipine was elucidated by parallel artificial membrane permeability assay (PAMPA) and full atomistic molecular dynamics (MD) simulation with free energy calculations. PAMPA experiments show a remarkable increase in the amount of nifedipine (NF) permeated with glycyrrhizin compared to free NF. In previous studies, we have shown using MD techniques that glycyrrhizin molecules can integrate into the lipid bilayer. In this study, MD simulation demonstrates a significant decrease in the energy barrier of NF penetration through the lipid bilayer in the presence of glycyrrhizin both in the pure DOPC membrane and in the membrane with cholesterol. This effect can be explained by the formation of hydrogen bonds between NF and GA in the middle of the bilayer.
AB - The saponin glycyrrhizin from liquorice root shows the ability to enhance the therapeutic activity of other drugs when used as a drug delivery system. Due to its amphiphilic properties, glycyrrhizin can form self-associates (dimers, micelles) and supramolecular complexes with a wide range of hydrophobic drugs, which leads to an increase in their solubility, stability and bioavailability. That is why the mechanism of the biological activity of glycyrrhizin is of considerable interest and has been the subject of intensive physical and chemical research in the last decade. Two mechanisms have been proposed to explain the effect of glycyrrhizin on drug bioavailability, namely, the increase in drug solubility in water and enhancement of the membrane permeability. Interest in the membrane-modifying ability of glycyrrhizic acid (GA) is also growing at present due to its recently discovered antiviral activity against SARS-CoV-2 Bailly and Vergoten (2020) [1]. In the present study, the passive permeability of the DOPC lipid membrane for the calcium channel blocker nifedipine was elucidated by parallel artificial membrane permeability assay (PAMPA) and full atomistic molecular dynamics (MD) simulation with free energy calculations. PAMPA experiments show a remarkable increase in the amount of nifedipine (NF) permeated with glycyrrhizin compared to free NF. In previous studies, we have shown using MD techniques that glycyrrhizin molecules can integrate into the lipid bilayer. In this study, MD simulation demonstrates a significant decrease in the energy barrier of NF penetration through the lipid bilayer in the presence of glycyrrhizin both in the pure DOPC membrane and in the membrane with cholesterol. This effect can be explained by the formation of hydrogen bonds between NF and GA in the middle of the bilayer.
KW - DOPC
KW - Drug delivery
KW - Glycyrrhizin
KW - Lipid bilayer
KW - Membrane penetration
KW - Molecular dynamics
KW - Nifedipine
KW - NMR
KW - PAMPA
UR - http://www.scopus.com/inward/record.url?scp=85117194853&partnerID=8YFLogxK
U2 - 10.1016/j.molliq.2021.117759
DO - 10.1016/j.molliq.2021.117759
M3 - Article
C2 - 34658466
AN - SCOPUS:85117194853
VL - 344
JO - Journal of Molecular Liquids
JF - Journal of Molecular Liquids
SN - 0167-7322
M1 - 117759
ER -
ID: 34464086